Chronic Kidney Disease Trial Research Articles

Quality of life in people with chronic kidney disease: focusing on modifiable risk factors.

With ageing populations and rising prevalence of key risk factors, the prevalence of many long-term conditions including chronic kidney disease (CKD) is increasing globally. Health-related quality of life (HRQoL) is important to people living with CKD but not all HRQoL determinants are modifiable. This review summarizes recently identified potentially modifiable factors affecting HRQoL for people with CKD and recent trials incorporating HRQoL as an outcome. Considering a broad definition of 'potentially modifiable', many factors have been associated with HRQoL in recent observational studies. These include mental health conditions, symptoms, medications, health behaviours, weight-related issues, poor social support, lower education, limited literacy and directly CKD- related factors such as anaemia. Some potentially modifiable factors have been tested in CKD trials, though often with HRQoL as a secondary outcome, so may be underpowered for HRQoL. Interventions with evidence of effect on HRQoL include physical activity, education, some nutritional interventions and medications targeting CKD-related anaemia. Clinicians should consider the range of potentially modifiable factors influencing HRQoL as part of a holistic approach to CKD care. High-quality, adequately-powered trials, with HRQoL as a primary outcome, with interventions focusing on the other potentially modifiable factors identified are needed.

Assessing Cognition in CKD Using the National Institutes of Health Toolbox.

Chronic kidney disease (CKD) is largely an age-related clinical disorder with accelerated cognitive and cardiovascular aging. Cognitive impairment is a well-documented occurrence in midlife and older adults with CKD and affects multiple domains. We examined cognition function and potential sex differences in cognition in adults with CKD. We included 105 individuals (49.5% women) with CKD stage 3b-4 (eGFR 15-44 mL/min) from the Bicarbonate Administration in CKD Trial (NCT02915601). We measured cognitive function using the National Institutes of Health (NIH) Toolbox® Cognition Battery, which assesses cognitive and motor measures such as executive function, attention, memory, and dexterity. All study measures were collected and analyzed at the study baseline. The mean (SD) age and eGFR were 61 ± 12 years and 34.9 ± 9.8 mL/min/1.73m2. Overall, when compared to the NIH Toolbox reference population, participants scored, on average, below the 50th percentile across all cognitive domain tests and the dexterity test. Total cognition scores were also below the 50th percentile. Participants with stage 4 CKD had significantly lower fluid cognition scores compared to those with CKD stage 3b (β-Estimate -5.4 (95% CI-9.8 to -0.9); p=0.03). Female participants with CKD performed significantly better on the episodic memory tests and dexterity tests (dominant and non-dominant pegboard tests), and had higher crystallized cognition scores, on average, compared to males. Participants with CKD had detectable cognitive deficits in fluid cognition, dexterity, and total cognition. Additionally, sex differences in cognitive measures were found among people with CKD.

Comparing Bayesian hierarchical meta-regression methods and evaluating the influence of priors for evaluations of surrogate endpoints on heterogeneous collections of clinical trials

BackgroundSurrogate endpoints, such as those of interest in chronic kidney disease (CKD), are often evaluated using Bayesian meta-regression. Trials used for the analysis can evaluate a variety of interventions for different sub-classifications of disease, which can introduce two additional goals in the analysis. The first is to infer the quality of the surrogate within specific trial subgroups defined by disease or intervention classes. The second is to generate more targeted subgroup-specific predictions of treatment effects on the clinical endpoint.MethodsUsing real data from a collection of CKD trials and a simulation study, we contrasted surrogate endpoint evaluations under different hierarchical Bayesian approaches. Each approach we considered induces different assumptions regarding the relatedness (exchangeability) of trials within and between subgroups. These include partial-pooling approaches, which allow subgroup-specific meta-regressions and, yet, facilitate data adaptive information sharing across subgroups to potentially improve inferential precision. Because partial-pooling models come with additional parameters relative to a standard approach assuming one meta-regression for the entire set of studies, we performed analyses to understand the impact of the parameterization and priors with the overall goals of comparing precision in estimates of subgroup-specific meta-regression parameters and predictive performance.ResultsIn the analyses considered, partial-pooling approaches to surrogate endpoint evaluation improved accuracy of estimation of subgroup-specific meta-regression parameters relative to fitting separate models within subgroups. A random rather than fixed effects approach led to reduced bias in estimation of meta-regression parameters and in prediction in subgroups where the surrogate was strong. Finally, we found that subgroup-specific meta-regression posteriors were robust to use of constrained priors under the partial-pooling approach, and that use of constrained priors could facilitate more precise prediction for clinical effects in trials of a subgroup not available for the initial surrogacy evaluation.ConclusionPartial-pooling modeling strategies should be considered for surrogate endpoint evaluation on collections of heterogeneous studies. Fitting these models comes with additional complexity related to choosing priors. Constrained priors should be considered when using partial-pooling models when the goal is to predict the treatment effect on the clinical endpoint.

Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers and health professionals.

Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in chronic kidney disease (CKD), which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. This was an online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals who could read English, Spanish or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a Best-Worst Scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. In total, 1399 participants from 73 countries completed Round 1 of the Delphi survey, including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization and cardiovascular disease (mean difference >0.3). Consensus was based upon the two groups yielding median scores of ≥7 and mean scores >7, and the proportions of both groups rating the outcome as 'critically important' being >50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. Across trials in CKD, the outcomes of highest priority to patients, caregivers and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death.

Gender Disparities in Nephrology Trials: A Meta-Analysis of Enrollment Trends between 2000 and 2021.

Gender disparities in the incidence and complications of kidney diseases are well described. However, analysis to elucidate gender disparities in enrollment in nephrology randomized clinical trials (RCTs) has not been performed. We performed a systematic review and meta-analysis of high impact nephrology RCTs published between 2000-2021. We. included RCTs enrolling participants age ≥18 in the following categories: 1) chronic kidney disease (CKD); 2) acute kidney injury (AKI); 3) glomerulonephritis (GN); 4) maintenance dialysis; and 5) kidney transplantation. We summarized trial characteristics according to reporting and enrollment of participants, enrollment site, publication year, trial category, and intervention type. Outcomes of interest include the proportion of enrolled male and female participants overall and according to trial category. Additionally, we compared enrollment trends in the United States and globally to estimates of kidney disease prevalence. The majority of qualifying trials (373/380, 98%) reported the distribution of male and female participants. Enrollment was imbalanced overall with male participants accounting for 62% (n=215,850) of the enrolled participants and female participants for just 38% (n=133,082). Male participants formed the majority of trial cohorts in AKI (65%), CKD (62%), Dialysis (55%) and transplant trials (65%), whereas women were majority enrollees in glomerulonephritis trials (61%). CKD trials under-represented women in both US trials and worldwide. Women are under-represented in high impact nephrology trials with the exception of GN trials. This imbalance may contribute to disparities in outcomes and gaps in the care of women with kidney disease.

Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease.

Chronic kidney disease (CKD) is a global health problem with rising incidence and prevalence. Among several pathogenetic mechanisms responsible for disease progression, lipid accumulation in the kidney parenchyma might drive inflammation and fibrosis, as has been described in fatty liver diseases. Lipids and their metabolites have several important structural and functional roles, as they are constituents of cell and organelle membranes, serve as signalling molecules and are used for energy production. However, although lipids can be stored in lipid droplets to maintain lipid homeostasis, lipid accumulation can become pathogenic. Understanding the mechanisms linking kidney parenchymal lipid accumulation to CKD of metabolic or non-metabolic origin is challenging, owing to the tremendous variety of lipid species and their functional diversity across different parenchymal cells. Nonetheless, multiple research reports have begun to emphasize the effect of dysregulated kidney lipid metabolism in CKD progression. For example, altered cholesterol and fatty acid metabolism contribute to glomerular and tubular cell injury. Newly developed lipid-targeting agents are being tested in clinical trials in CKD, raising expectations for further therapeutic development in this field.

Chronic kidney disease: the missing concept in the 2019 EULAR/ERA-EDTA recommendations for lupus nephritis.

Chronic kidney disease (CKD) is diagnosed when glomerular filtration rate (GFR) falls below 60ml/min/1.73m2 or urinary albumin:creatinine ratio (UACR) reaches ≥30mg/g, as these two thresholds indicate a higher risk of adverse health outcomes, including cardiovascular mortality. CKD is classified as mild, moderate or severe, based on GFR and UACR values, and the latter two classifications convey a high or very high cardiovascular risk, respectively. Additionally, CKD can be diagnosed based on abnormalities detected by histology or imaging. Lupus nephritis (LN) is a cause of CKD. Despite the high cardiovascular mortality of patients with LN, neither albuminuria nor CKD are discussed in the 2019 European League Against Rheumatism (EULAR)/European Renal Association-European Dialysis and Transplant Association recommendations for the management of LN or the more recent 2022 EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases. Indeed, the proteinuria target values discussed in the recommendations may be present in patients with severe CKD and a very high cardiovascular risk who may benefit from guidance detailed in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice. We propose that the recommendations should move from a conceptual framework of LN as an entity separate from CKD to a framework in which LN is considered a cause of CKD and evidence generated from large CKD trials applies unless demonstrated otherwise.

Women's representation in clinical trials of patients with chronic kidney disease.

Sex and gender differences in chronic kidney disease (CKD), including epidemiology and response to treatment, remain poorly understood. This study aimed to investigate how women are represented in CKD clinical trials and whether sex- and gender-disaggregated outcomes were reported. Clinical trials on CKD were identified from ClinicalTrials.gov. Randomised, phase 3/4 trials with ≥100 participants were selected to quantify women's representation among participants by computing the participation:prevalence ratio (PPR) and investigating whether sex-disaggregated analyses had been performed. In total, 192 CKD trials registered on ClinicalTrials.gov and published between 1995 and 2022 were included. Overall, women accounted for 66875 (45%) of the 147136 participants. Women's participation in clinical trials was lower than their representation in the underlying CKD population globally (55%). The PPR was 0.75 (95% confidence interval 0.72-0.78), with no significant variation irrespective of mean age, CKD stage, dialysis, location, type of intervention or funding agency. A total of 39 (20%) trials reported sex-disaggregated efficacy outcomes and none reported sex-disaggregated safety outcomes. Women's participation in CKD clinical trials was lower than their representation in the underlying CKD population. Sex-disaggregated efficacy and safety outcomes were rarely reported. Improving women's enrolment into clinical trials is crucial to enable sex- and gender-disaggregated analysis and thus identify potential differences in treatment response between women and men.

Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study.

To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT). We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200-5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs. The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54-0.96; P = 0.025). Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination.

Race, Sex, and Kidney Disease Trial Participation

Race, Sex, and Kidney Disease Trial Participation

Value of SGLT-2 inhibitors in the treatment of chronic kidney disease : Clinical and practical implications.

Chronic kidney disease (CKD) drastically increases the risk for cardiovascular morbidity and mortality and its worldwide prevalence is still rising. Effective treatment slows CKD progression, prevents development of end-stage kidney disease and cardiovascular disease thereby prolonging survival of patients. Recently, several large-scale studies with sodium-glucose cotransport‑2 inhibitors (SGLT-2i) have demonstrated profound nephroprotective and cardioprotective properties in patients with type2diabetes mellitus with both CKD and heart failure. Recently, the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial demonstrated that the selective SGLT-2i dapagliflozin reduced the hazard ratio for acomposite renal and cardiovascular death endpoint in patients with CKD with or without type2diabetes. Furthermore, dapagliflozin exerted strong nephroprotection in CKD patients with diverse etiologies like IgA nephropathy. Furthermore, other promising CKD trials such as with empagliflozin are underway. Hence, individualized treatment with SGLT2i represents apromising therapeutic option for patients with both diabetic and non-diabetic CKD. Here we summarize the current knowledge on the treatment with SGLT-2i in CKD patients underscoring astrong rationale for SGLT2 inhibition to be incorporated into standard of care for most CKD patients also with non-diabetic kidney disease. Finally, we aim to translate the current evidence into recommendations for the clinical practice in the management of patients with CKD.

Expert consensus on the treatment of chronic kidney disease with tuberculosis (2022 version)

China is a country with a high burden of chronic kidney disease(CKD) and tuberculosis. Patients with CKD are at increased risk of Mycobacterium tuberculosis infection, and the prevalence of CKD is also significantly higher in patients with tuberculosis. The coexistence of the two diseases brings great difficulties for clinical treatment. In this consensus, the general situation, clinical characteristics, metabolic characteristics of anti-tuberculous drugs, and the principles of protocol formulation of such patients were discussed and summarized. When making anti-tuberculosis regimen for patients with chronic renal failure, drugs that metabolized through liver, liver and kidney channels or metabolic pathways other than liver and kidney should be selected as far as possible. Drugs with significant renal toxicity and mainly metabolized by the kidney should be avoided. For CKD patients with mild decrease in GFR (60-89 ml·min-1·1.73 m-2), anti-tuberculosis regimen should be carried out according to the national standards and guidelines, without reducing the dose of anti-tuberculosis drugs. For CKD patients with significantly reduced GFR, mainly CKD3b, stages 4-5, and those receiving dialysis, the anti-tuberculosis regimen must be adjusted according to the GFR. For CKD patients with GFR less than 30 ml·min-1·1.73 m-2, this consensus also recommended anti-tuberculous regimen for initial, retreated and multi-drug-resistant tuberculosis patients. This consensus aimed to improve clinicians' understanding of CKD complicated with tuberculosis, standardize the clinical treatment, improve the curative effect, and reduce adverse reactions. Data from previous trials of CKD combined with TB treatment are still scarce. We look forward to further investigation and evidence-based medical research on CKD with tuberculosis in the future, and make positive efforts for the control of CKD and tuberculosis in China.

SGLT2 Inhibitors in the Management of Chronic Kidney Disease: An Expert Consensus.

Despite the availability of multiple therapies for chronic kidney disease (CKD), there still exists an unmet need for better options to slow down disease progression and prevent complications. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial, which demonstrated the renoprotective effects of the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin, independent of diabetes, with improved survival, even in patients with CKD with estimated glomerular filtration rate (eGFR) as low as 25 mL/min/1.73 m2 , has highlighted the potential beneficial role of SGLT2i in patients with CKD. These benefits were also achieved in patients who were already receiving optimal therapies for slowing the progression of CKD. The potential candidature of SGLT2i for CKD therapy is now being widely discussed in the nephrology community. Therefore, a consensus meeting was held in September 2020 with a group of expert nephrologists from India, to discuss the need to improve CKD management and assess the position of SGLT2i, based on compelling evidence from recent studies. This document summarizes the expert opinions and views on the position of SGLT2i in CKD management and aims to enhance the current understanding of the applicability of SGLT2i in patients with CKD. This will aid nephrologists and physicians across the country in decision-making on the management of patients with CKD using SGLT2i. Keywords: Chronic kidney disease, Dapagliflozin, Estimated glomerular filtration rate, SGLT2i inhibitors, Type 2 diabetes mellitus.

Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases: A Scientific Workshop Cosponsored by the National Kidney Foundation and the US Food and Drug Administration

In the past decade, advances in the validation of surrogate end points for chronic kidney disease (CKD) progression have heightened interest in evaluating therapies in early CKD. In December 2020, the National Kidney Foundation sponsored a scientific workshop in collaboration with the US Food and Drug Administration (FDA) to explore patient, provider, and payor perceptions of the value of treating early CKD. The workshop reviewed challenges for trials in early CKD, including trial designs, identification of high-risk populations, and cost-benefit and safety considerations. Over 90 people representing a range of stakeholders including experts in clinical trials, nephrology, cardiology and endocrinology, patient advocacy organizations, patients, payors, health economists, regulators and policy makers attended a virtual meeting. There was consensus among the attendees that there is value to preventing the development and treating the progression of early CKD in people who are at high risk for progression, and that surrogate end points should be used to establish efficacy. Attendees also concluded that cost analyses should be holistic and include aspects beyond direct savings for treatment of kidney failure; and that safety data should be collected outside/beyond the duration of a clinical trial. Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payors.

MO420: Effects of Indoxyl Sulfate and Apixaban in Liver Gene Expression

Abstract BACKGROUND AND AIMS Uraemic toxins accumulate in the blood and tissues of patients with chronic kidney disease (CKD). Previous animal studies have shown that chronic kidney disease (CKD) not only alters the elimination of drugs excreted by the kidneys, but it also impacts the metabolism of drugs subject to non-renal clearance, which involves mainly the liver and the gut. The use of apixaban, an oral anticoagulant, has been approved in the USA for dialysis patients. However, the coexistence of thrombotic and haemorrhagic risk in patients with CKD makes dose adjustment difficult. The liver has a major role in drug metabolization. Hepatocytes express high levels of AhR, a ligand-inducible transcription factor that mediates the induction of various liver cytochrome P450 enzymes by xeno and endobiotic. Tryptophan-derived uraemic toxins (TDUT) are AhR agonists. Indoxyl sulfate (IS) is the main TDUT involved in uraemic syndrome. IS increases the expression and activity of P-glycoprotein (P-gp) in the liver. Apixaban metabolism is mediated by P-gp and Cyp3a4 (Cyp3a11 in mice). We aim to study the effect of apixaban and IS in the expression of drug metabolism genes. Our hypothesis is that AhR activation by IS could severely modify drug metabolism during CKD. METHOD C57BL/6J Wild-type mice purchased from The Jackson Laboratory were fed ad libitum with a standard diet. At 10 weeks of age, mice drinking water was substituted with a 5% sucrose water solution with either 0.1% indoxyl sulphate or KCl (control) added at equivalent concentrations. 48-h before sacrifice some mice were gavaged with an apixaban solution (0.6 mg/mL) twice a day with the last dose given 4 h prior to sacrifice. All mice were sacrificed at 11 weeks of age. Liver samples were stored in an RNA-later solution at −20°C. Samples were thawed and lysed in Trizol using the Tissue-Ruptor system (Qiagen). RNA was extracted and purified with chloroform and precipitated with isopropanol. RNA concentration was estimated by spectrophotometry. Gene expression was analysed by q-RT-PCR using Gusb as a housekeeping gene. Apixaban levels were quantified by LC-MS. Kruskal–Wallis followed by a two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli (q < 0.05) was performed using GraphPad Prism 9.2.1. RESULTS Four groups of mice per sex were thus created: WT-KCl, WT-IS, WT-KCl Apix, WT-IS Apix. In the IS/KCl model we observe higher mRNA basal expression of Abcb1a (q = 0.008) and Sult1a1 (q = 0.006) and lower basal expression of Abcg2 (q = 0.0005) in females compared to males when treated with KCl. IS treatment increases Cyp1a2 expression in females (q = 0.0139) and Cyp1a1 in both males (q = 0.0145) and females (q = 0.026). In the IS/KCl-Apix model the same sex-related differences are maintained for Abcb1a (q = 0.0031), Sult1a1 (q = 0.0316) and Abcg2 (q < 0.0001). In males, CYP2e1 expression is increased by apixaban in KCl (q = 0.067) and IS (q = 0.0278) treated mice. Moreover, apixaban counteracts the increased expression of Cyp1a1 induced by IS (q = 0.0177). The expression of Cyp3a11 is augmented in males treated with KCl-apixaban (q = 0.0143), an effect that seems to be reversed by IS (q = 0.0066). In females, apixaban has no effect in gene expression. Apixaban serum concentration is higher in KCl (q = 0.0350) and IS (q = 0.0019) treated females when compared to males. CONCLUSION The effect of IS as an agonist of AhR in the liver is confirmed by the increased expression of Cyp1a1. Apixaban provokes a remarkable increase of Cyp3a11 in male mice, which could lead to higher degradation rates decreasing its activity. IS seems to reverse this effect. This could lead to increased activity of apixaban during CKD which could derive in an increased risk of bleeding. Higher BCRP rates could explain lower rates of apixaban in male serum. Apixaban did not alter gene expression in females. Clinical trials in CKD are generally biased regarding sex (fewer women represented) possibly masking important sex-dependent drug adverse effects. Our results show great differences in basal expression of various genes, confirming the importance to study men and women separately with respect to drug metabolism.

The EX-FRAIL CKD trial: A pilot RCT of a home-based Exercise programme for pre-FRAIL and FRAIL, older adults with CKD

Purpose: Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes. However, exercise training may improve physical function leading to associated improvements in outcomes. The EX-FRAIL CKD trial (ISRCTN87708989) aimed to inform the design of a randomised controlled trial (RCT) that investigates the efficacy of a progressive home-based exercise programme in pre-frail and frail older adults with CKD.

Comparison of chronic kidney disease trial designs and analysis strategies.

BackgroundDespite the large burden of chronic kidney disease (CKD), it is challenging to conduct adequately powered clinical trials in this setting. Sound and efficient trials are needed to advance treatment. Various analysis strategies can be used to compare the efficacy of a parallel trial design with that of three two period trial designs.MethodsThe type 1 error rates and powers of various trial designs were calculated using simulated data from models fit to two recent CKD trials. In addition, we assessed the influences of a variety of analysis strategies and of the presence of a carryover effect.ResultsThe parallel and crossover designs (with analysis of change from baseline to the off treatment value) maintained the target type 1 error rate in all scenarios. In some scenarios, an open label design yielded inflated type 1 error rates. In many scenarios, the open label and delayed start designs had unacceptably low power and high type 1 error rates. Overall, the crossover design had the highest power by far, and always controlled the type 1 error rate.ConclusionThe recommended approach to a CKD trial is a two period design with an endpoint that is the rate of change in estimated glomerular filtration rate from pretreatment to off treatment. As compared to a parallel trial, a crossover study involves a considerably smaller sample size and shorter total follow-up duration. A crossover design may also be preferable for patients, and facilitates recruitment of a sufficient number of subjects.

Hypertension Management in Patients with Chronic Kidney Disease in the Post-SPRINT Era.

The management of high blood pressure (BP) is crucial for improving outcomes in patients with chronic kidney disease (CKD). The updated Kidney Disease: Improving Global Outcomes 2021 BP guideline proposes treating adults with CKD to a target systolic BP (SBP) of <120 mmHg based on the standardized office BP measurement. This suggestion is largely based on the finding of SPRINT (Systolic Blood Pressure Intervention Trial) that targeting an SBP of <120 mmHg versus <140 mmHg is beneficial for cardiovascular and mortality outcomes, regardless of the patient’s kidney disease status. However, extended follow-up studies of CKD trials showed that intensive versus usual BP control was associated with a lower risk of kidney failure in patients with, but not in those without, proteinuria. Similarly, a recent population-based study in Korea demonstrated that the optimal on-treatment BP for composite cardiorenal and mortality outcomes was left-shifted in adults with CKD, particularly in those with albuminuria, relative to that in patients without CKD. Moreover, in meta-analyses of randomized trials, more intensive versus standard BP control was associated with a lower risk of all-cause mortality in patients with CKD and albuminuria but not in those without CKD. Meanwhile, a 2020 Cochrane review reported that lower BP targets (≤135/85 mmHg), compared with standard targets (≤140/90 mmHg), resulted in a small reduction in cardiovascular events, an increase in other serious adverse events, and no reduction in total serious adverse events. Lowering SBP to <120 mmHg can potentially increase the risk of treatment-related adverse events beyond the cardioprotective benefits, and standardized BP measurement increases the burden on patients and resources. Thus, targeting a BP of <130/80 mmHg with appropriate office BP measurement can be an option in patients with CKD. The presence of albuminuria would need to be additionally considered to determine individualized BP targets.

P0958THE EX-FRAIL CKD TRIAL: A PILOT RANDOMISED CONTROLLED TRIAL OF A HOME-BASED EXERCISE PROGRAMME FOR PRE-FRAIL AND FRAIL, OLDER ADULTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes. However, exercise training may improve physical function leading to associated improvements in outcomes. The EX-FRAIL CKD trial (ISRCTN87708989) aimed to inform the design of a randomised controlled trial (RCT) that investigates the efficacy of a progressive home-based exercise programme in pre-frail and frail older adults with CKD. Methods Patients aged ≥65 years with CKD G3b-5 and a Clinical Frailty Scale score ≥4 were eligible for participation. Participants categorised as pre-frail or frail, following Frailty Phenotype (FP) assessment, were randomised to receive a tailored 12-week home-based exercise programme or usual care (UC). Primary outcome measures included recruitment, intervention adherence, outcome measure completion and participant attrition rate. Secondary outcome measures included frailty status (FP), physical function (walking speed, handgrip strength and Short Physical Performance Battery [SPPB]), fall concern (Falls Efficacy Scale-International tool [FESI]), symptom-burden (Palliative Care Outcome Scale-Symptoms RENAL [POS-S RENAL]) and health-related quality of life (Short Form-12v2 [SF-12]). Outcome measures are reported descriptively with 95% confidence intervals (CI) as recommended for pilot trials. Progression criteria to RCT stage were defined as: (1) eligibility: STOP &amp;lt;5%, GO &amp;gt;10%; (2) recruitment: STOP &amp;lt;10%, GO &amp;gt;30%; (3) exercise adherence: STOP: &amp;lt;30%, GO &amp;gt;70%; (4) outcome measure completion: STOP &amp;lt;70%, GO &amp;gt;80%; and (5) loss to follow-up: STOP &amp;gt;50%, GO &amp;lt;25%. Results Six hundred and sixty-five participants had an eligibility assessment with 201 (30% [95% CI 27-34]) patients eligible for enrolment. Thirty-five (17% [95% CI 12-23]) participants were recruited. Six participants were categorised as robust and therefore withdrawn prior to randomisation. Fifteen participants were randomised to exercise (mean age 77.0±8.3 years; mean eGFR 18.9±7.0 ml/min/1.73m2) and 14 to UC (mean age 78.8±7.0 years; mean eGFR 20.4±7.2 ml/min/1.73m2). Eleven (73% [95% CI 45-92]) exercise group participants completed an average of ≥2 exercise sessions/week. Eight (28% [95% CI 13-47]) participants were lost to follow-up. Retained participants (n=21, 100% [95% CI 84-100]) completed all outcome measures. There were 32 adverse events in the exercise group and 22 in the UC group. Within the exercise group, there were 2 hospitalisations (considered unrelated to exercise) and 12 adverse reactions: musculoskeletal pain (9), fall (1), nocturnal leg cramps (1) and postural dizziness (1). The odds ratio for improvement in frailty status with exercise was 5.50 (95% CI 0.46-65.16) and odds ratio for deterioration in frailty status was 0.63 (95% CI 0.05-8.20). The adjusted mean group difference in walking speed, grip strength and SPPB between exercise and UC groups were: 0.01 metres/second (95% CI -0.07-0.10), 3.6 kg (95% CI -0.6-7.9) and 0.5 (95% CI -0.9-1.8), respectively. The adjusted mean group difference in POS-S RENAL, FESI, SF-12 Physical Component Summary and SF-12 Mental Component Summary scores were: -1.4 (95% CI -6.6-3.7), 3.4 (95% CI -3.5-10.3), -3.9 (95% CI -9.3-1.5) and 0.2 (95% CI -6.2-6.6), respectively. Conclusion Eligibility, adherence and outcome measure progression criteria thresholds were exceeded; however, recruitment and loss to follow-up progression criteria thresholds were not achieved. Analysis of a nested qualitative study will explore perceived barriers to participation and retention. The EX-FRAIL CKD trial demonstrates that it is possible to progress to a definitive RCT with adaptations that address the barriers described. It has also provided preliminary evidence that frailty status and physical function may be improved with a home-based exercise programme in patients living with frailty and CKD.

The EX-FRAIL CKD trial: a study protocol for a pilot randomised controlled trial of a home-based EXercise programme for pre-frail and FRAIL, older adults with Chronic Kidney Disease

IntroductionFrailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes including falls, poorer health-related quality of life (HRQOL), hospitalisation and mortality. Low...